ESR1 Mutation in Endocrine Treatment-Naïve Endometrial Cancer: Prevalence, Characteristics, and Prognostic Implications, Results from the UTOLA Phase II GINECO Trial.
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Blanc-Durand Félix, Genestie Catherine, Nikolaev Sergey, Leman Raphael, Church David N, Beinse Guillaume, Tredan Olivier, Bengrine Lefevre Leïla, Brachet Pierre-Emmanuel, Lebreton Coriolan, Meynard Guillaume, Fournel Pierre, Frenel Jean-Sébastien, Selle Frédéric, Cornila Corina, Fernandez Diez Yolanda, Bonnet Elise, Arnaud Antoine, Kaczmarek Emilie, Follana Philippe, Hardy-Bessard Anne-Claire, Fabbro Michel, Cojean Zelek Isabelle, Roche Sophie, Duliege Delphine, Mouret-Reynier Marie Ange, Bouchaert Patrick, Alexandre Jérôme, Joly Florence, Leary Alexandra
Аннотация
EXPERIMENTAL DESIGN: A total of 147 patients with advanced endometrial cancer who had responded to first-line chemotherapy were recruited into the UTOLA trial. Archival endometrial cancer tumor tissues underwent sequencing of 127 genes, including ESR1. Only hotspot mutations in the ligand-binding domain were evaluated. ESR1 mutation prevalence was validated in the Genomics England dataset. In UTOLA, tumors were classified as POLE, MMR deficient, TP53abn, or no specific molecular profiles (NSMP) based on the Proactive Molecular Risk Classifier for Endometrial Cancer (PROMISE) classification.
RESULTS: Of 147 patients, 137 had sufficient tumor material for sequencing. ESR1 mutations were identified in eight tumors (6%), including Y537S/C/N (n = 4), L536H/P (n = 2), and E380Q (n = 2). A similar prevalence (3.5%) was found among 1,311 tumors in the Genomics England dataset. All ESR1 mutation cases were low-grade endometrioid endometrial cancer, ER-positive, and PR-positive, and classified as NSMP. Among patients with metastatic NSMP low-grade endometrioid endometrial cancer, 22% (8/37) harbored ESR1 mutations. Survival outcomes after platinum chemotherapy were similar between patients with ESR1 mutation endometrial cancer and ESR1 wild type (median, not reached vs. 25.3 months; P = 0.114).
CONCLUSIONS: ESR1 mutations, while rare overall in treatment-naïve endometrial cancer, are more prevalent in patients with NSMP low-grade endometrioid endometrial cancer, potentially affecting AI efficacy. ESR1 status should be considered in selecting hormonotherapy and as a stratification factor in AI trials.